DIFFERENTIAL-EFFECTS OF ANGIOTENSIN-II AND TRANSFORMING GROWTH-FACTOR-BETA ON THE PRODUCTION OF HEPARAN-SULFATE PROTEOGLYCAN BY MESANGIAL CELLS IN-VITRO

This study approaches the question of whether angiotensin II (AngII) a nd transforming growth factor beta (TGF-beta) are important mediators for mesangial heparan sulfate proteoglycan (HSPG) production, This mig ht explain the beneficial effects of angiotensin-converting enzyme inh ibitors observed in several kidney diseases independent from their hem odynamic effects. Metabolic-labeling studies revealed that AngII induc ed a decrease of HSPG synthesis with decreases in N-sulfation of the g lycosaminoglycan side chains. ELISA measurements with a heparan sulfat e (HS)-specific monoclonal antibody confirmed that AngII decreased HS production, AngII increased TGF-beta production in a dose-dependent fa shion. Specific mRNA for the large basement membrane HSPG (perlecan) d ecreased, whereas mRNA for TGF-beta increased after incubation with An gII. Blockade of the Subtype 1 Ang-ll receptor (ATR1) reversed both th e effects of AngII on HSPG and TGF-beta production. Coincubation of th e mesangial cells with neutralizing antibodies against TGF-beta signif icantly reduced the production of HS as compared with control and AngI I. These results indicate that the decrease in HS synthesis induced by AngII is not mediated by an increase in TGF-beta, but on the contrary , the increase in TGF-beta partially counteracts the inhibition of HS production by AngII. Considering the important role of HSPG in maintai ning the glomerular charge barrier, cell proliferation, and matrix int eraction, downregulation of the production of this molecule by increas ed local AngII concentrations could have important consequences, such as albuminuria and matrix expansion.